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We thank Dr. Suarez-Barrientos and colleagues1 for their comments regarding our recent manuscript entitled “Circadian Dependence of Infarct Size and Left-Ventricular Function After ST-Elevation Myocardial Infarction.”2 Our clinical investigation was stimulated by the findings of Durgan et al,3 who demonstrated a circadian dependence to the tolerance of ischemia/reperfusion injury (infarct size) in the rodent heart. Although the title of our article and that of Dr. Suarez-Barrientos and colleagues4 are similar, we believe that the 2 studies are reporting 2 different and distinct clinical observations that may have resulted in the different times of peak infarct size.

Suarez-Barrientos et al4 observed that peak infarct size was highest between 6 am and noon in 811 patients as measured by CK and troponin in four 6-hour intervals, while we observed that the largest myocardial injury occurred between 1 and 5 am. While we utilized a continuous “circadian” statistical model with periodic sinusoidal regression analysis, they used multivariate regression splines. We acknowledge that both methods have limitations; however, the spline model is subject to several arbitrary decisions such as number of splines and where knots are placed.

In contrast to their study, our investigation was specifically designed to determine if a circadian tolerance to ischemia/reperfusion injury occurs in the human heart. To answer that question, it was necessary to obtain accurate data of infarct size, area at risk, and ischemic duration. It is not clear to us how ischemic times could be accurately determined in their study, since ischemic duration and time of reperfusion could not be determined in the many of their patients due to significant numbers receiving reperfusion with fibrinolysis alone. In contrast, all patients in our study had occluded arteries on presentation for primary PCI, allowing for a more accurate determination of ischemic duration. Additionally, no measurements were made to determine the area at risk of the infarct vessel territory in their study.

We fully agree that our highly selected cohort played a role in our final results, but that was by design. We prospectively required patients to have ischemic times between 1 and 6 hours and be free of infarct-sparing mechanisms such as preinfarction angina or visible collateral blood flow. These limitations were not imposed in the study of Suarez-Barrientos.4 Our methodology created the required homogeneous patient population necessary to investigate the provocative preclinical findings of Durgan et al,3 and we believe that this approach would be superior to statistical manipulation of the data by multivariate analysis.

Although peak troponin was available in 105 of the 165-patient cohort and showed a similar circadian distribution of peak infarct size, we elected not to show these data in the manuscript since we had demonstrated an excellent correlation between peak CK and infarct size as measured by cardiac MRI in our study.